Metalloenzyme inhibitor compounds

ABSTRACT

The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/US2012/052483, filed Aug. 27, 2012,which claims the benefit of U.S. Provisional Patent Application No.61/528,953, filed Aug. 30, 2011, the entire contents of theaforementioned applications are hereby incorporated herein by reference.

BACKGROUND

Living organisms have developed tightly regulated processes thatspecifically imports metals, transport them to intracellular storagesites and ultimately transport them to sites of use. One of the mostimportant functions of metals such as zinc and iron in biologicalsystems is to enable the activity of metalloenzymes. Metalloenzymes areenzymes that incorporate metal ions into the enzyme active site andutilize the metal as a part of the catalytic process. More thanone-third of all characterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence ofthe metal ion in the active site of the enzyme. It is well recognizedthat agents which bind to and inactivate the active site metal iondramatically decrease the activity of the enzyme. Nature employs thissame strategy to decrease the activity of certain metalloenzymes duringperiods in which the enzymatic activity is undesirable. For example, theprotein TIMP (tissue inhibitor of metalloproteases) binds to the zincion in the active site of various matrix metalloprotease enzymes andthereby arrests the enzymatic activity. The pharmaceutical industry hasused the same strategy in the design of therapeutic agents. For example,the azole antifungal agents fluconazole and voriconazole contain a1-(1,2,4-triazole) group that binds to the heme iron present in theactive site of the target enzyme lanosterol demethylase and therebyinactivates the enzyme. Another example includes the zinc-bindinghydroxamic acid group that has been incorporated into most publishedinhibitors of matrix metalloproteinases and histone deacetylases.Another example is the zinc-binding carboxylic acid group that has beenincorporated into most published angiotensin-converting enzymeinhibitors.

In the design of clinically safe and effective metalloenzyme inhibitors,use of the most appropriate metal-binding group for the particulartarget and clinical indication is critical. If a weakly bindingmetal-binding group is utilized, potency may be suboptimal. On the otherhand, if a very tightly binding metal-binding group is utilized,selectivity for the target enzyme versus related metalloenzymes may besuboptimal. The lack of optimal selectivity can be a cause for clinicaltoxicity due to unintended inhibition of these off-targetmetalloenzymes. One example of such clinical toxicity is the unintendedinhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19and CYP3A4 by the currently-available azole antifungal agents such asfluconazole and voriconazole. It is believed that this off-targetinhibition is caused primarily by the indiscriminate binding of thecurrently utilized 1-(1,2,4-triazole) to iron in the active site ofCYP2C9, CYP2C19 and CYP3A4. Another example of this is the joint painthat has been observed in many clinical trials of matrixmetalloproteinase inhibitors. This toxicity is considered to be relatedto inhibition of off-target metalloenzymes due to indiscriminate bindingof the hydroxamic acid group to zinc in the off-target active sites.

Therefore, the search for metal-binding groups that can achieve a betterbalance of potency and selectivity remains an important goal and wouldbe significant in the realization of therapeutic agents and methods toaddress currently unmet needs in treating and preventing diseases,disorders and symptoms thereof.

BRIEF SUMMARY OF THE INVENTION

The invention is directed towards compounds (e.g., any of thosedelineated herein), methods of modulating activity of metalloenzymes,and methods of treating diseases, disorders or symptoms thereof. Themethods can comprise the compounds herein.

A compound of formula (I), or salt, solvate, hydrate or prodrug thereof,wherein:

Each R¹ and R² is independently optionally substituted aryl, optionallysubstituted naphthyl, optionally substituted heteroaryl, optionallysubstituted alkyl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl, oroptionally substituted heteroaryl-alkyl;

R³ is H, OH, alkoxy, amino, alkylamino, or dialkylamino;

R⁴ is H or halo.

In another aspect, the compound is of formula (I), or salt, solvate,hydrate or prodrug thereof,

-   -   wherein the compound is of formula (I) is not:

and pharmaceutically acceptable salts, solvates, or hydrates thereof.

In one aspect, the compound of formula I is that wherein R₃ is OH.

In one aspect, the compound of formula I is that wherein R₂ isoptionally substituted alkyl, and R₃ is OH.

In one aspect, the compound of formula I is that wherein R₁ isoptionally substituted aryl, R₂ is alkyl, and R₃ is OH.

In one aspect, the compound of formula I is that wherein R₁ isoptionally substituted heteroaryl, R₂ is alkyl, and R₃ is OH.

In one aspect, the compound of formula I is that wherein R₁ issubstituted aryl, R₂ is alkyl, and R₃ is OH.

In one aspect, the compound of formula I is that wherein R₁ isoptionally substituted naphthyl, R₂ is alkyl, and R₃ is OH.

In one aspect, the compound of formula I is that wherein R₁ issubstituted naphthyl, R₂ is alkyl, and R₃ is OH.

In one aspect, the compound of formula I is that wherein R₁ is naphthylsubstituted with 1, 2, 3 or 4 substituents, independently selected fromalkyl, alkoxy, haloalkoxy, cyano, halo, amino, mono-alkylamino,di-alkylamino, or heteroaryl.

In one aspect, the compound of formula I is that wherein R₁ is aryloptionally substituted with 1, 2, 3 or 4 independent substituentsselected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano,nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl),carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl,thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl,dialkylamino, alkylcarbonylamino, alkylaminocarbonyl,alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl,or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl,amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, imino, carbamido, carbamyl,thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl,mercaptoalkoxy, N-hydroxyamidinyl, or N′-aryl, N″-hydroxyamidinyl

In one aspect, the compound of formula I is that having the structure offormula (II):

wherein each of R¹, R², R³ and R⁴ is as defined above, and R⁵ and R⁶ areindependently H, halogen, alkoxy, fluoroalkoxy containing 1-5 fluorines,cyano, carboxamido, optionally substituted aryl, or optionallysubstituted heteroaryl.

In one aspect, the compound of formula I is that wherein R⁴ is H.

In one aspect, the compound of formula I is that wherein R⁴ is halo.

In one aspect, the compound of formula I is that wherein R⁴ is chloro.

In one aspect, the compound of formula I is that wherein the compoundattains affinity for a metalloenzyme by formation of one or more of thefollowing types of chemical interactions or bonds to a metal: sigmabonds, covalent bonds, coordinate-covalent bonds, ionic bonds, pi bonds,delta bonds, or backbonding interactions.

In one aspect, the compound of formula I is that wherein the compoundbinds to a metal.

In one aspect, the compound of formula I is that wherein the compoundbinds to iron, zinc, heme iron, manganese, magnesium, iron sulfidecluster, nickel, molybdenum, or copper.

In one aspect, the compound of formula I is that wherein the compoundinhibits an enzyme class selected from cytochrome P450 family, histonedeacetylases, matrix metalloproteinases, phsophodiesterases,cycloxygenases, carbonic anhydrases, and nitric oxide synthases.

In one aspect, the compound of formula I is that wherein the compoundinhibits an enzyme selected from 4-hydroxyphenyl pyruvate dioxygenase,5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase,aminopeptidase n, angiotensin converting enzyme, aromatase (CYP19),calcineurin, carbamoyl phosphate synthetase, carbonic anhydrase family,catechol o-methyl transferase, cyclooxygenase family, dihydropyrimidinedehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyltransferase, fumarate reductase, GABA aminotransferase, HIF-prolylhydroxylase, histone deacetylase family, HIV integrase, HIV-1 reversetranscriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51),matrix metalloprotease family, methionine aminopeptidase, neutralendopeptidase, nitric oxide synthase family, phosphodiesterase III,phosphodiesteraseIV, phosphodiesteraseV, pyruvate ferredoxinoxidoreductase, renal peptidase, ribonucleoside diphosphate reductase,thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease,and xanthine oxidase.

In one aspect, the compound of formula I is that wherein the compoundinhibits an enzyme selected from 1-deoxy-d-xylulose-5-phosphatereductoisomerase (DXR), 17-alpha hydroxylase (CYP17), aldosteronesynthase (CYP11B2), aminopeptidase p, anthrax lethal factor, arginase,beta-lactamase, cytochrome P450 2A6, d-ala d-ala ligase, dopaminebeta-hydroxylase, endothelin converting enzyme-1, glutamatecarboxypeptidase II, glutaminyl cyclase, glyoxalase, heme oxygenase,HPV/HSV E1 helicase, indoleamine 2,3-dioxygenase, leukotriene A4hydrolase, methionine aminopeptidase 2, peptide deformylase,phosphodiesteraseVII, relaxase, retinoic acid hydroxylase (CYP26),TNF-alpha converting enzyme (TACE),UDP-(3-O—(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC),vascular adhesion protein-1 (VAP-1), and vitamin D hydroxylase (CYP24).

In one aspect, the compound of formula I is that wherein the compound isidentified as binding to a metal.

In one aspect, the compound of formula I is that wherein the compound isidentified as binding to iron, zinc, heme-iron, manganese, magnesium,iron-sulfide cluster, nickel, molybdenum, or copper.

In one aspect, the compound of formula I is that wherein the compound isidentified as inhibiting an enzyme class selected from cytochrome P450family, histone deacetylases, matrix metalloproteinases,phsophodiesterases, cycloxygenases, carbonic anhydrases, and nitricoxide synthases.

In one aspect, the compound of formula I is that wherein the compound isidentified as inhibiting an enzyme selected from 4-hydroxyphenylpyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcoholdehydrogenase, aminopeptidase n, angiotensin converting enzyme,aromatase (CYP19), calcineurin, carbamoyl phosphate synthetase, carbonicanhydrase family, catechol o-methyl transferase, cyclooxygenase family,dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphatesynthase, farnesyl transferase, fumarate reductase, GABAaminotransferase, HIF-prolyl hydroxylase histone deacetylase family, HIVintegrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase,lanosterol demethylase (CYP51), matrix metalloprotease family,methionine aminopeptidase, neutral endopeptidase, nitric oxide synthasefamily, phosphodiesterase III, phosphodiesteraseIV, phosphodiesteraseV,pyruvate ferredoxin oxidoreductase, renal peptidase, ribonucleosidediphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase,tyrosinase, urease, and xanthine oxidase.

In one aspect, the compounds herein are those wherein the compound isidentified as an inhibitor of CYP17.

In one aspect, the compounds herein are those wherein the compound isidentified as having an activity range against a target enzyme and anactivity range against an off-target enzyme (e.g., CYP17 IC50<0.35 uMand IC50>0.75 μM for CYP2C9, CYP2C19 and CYP3A4; CYP17 IC50<XX μM andIC50>YY μM for CYP2C9, CYP2C19 and CYP3A4, in each instance XX is anindependent number; in each instance YY is an independent number; incertain aspects XX is a number less than YY). In certain aspects, forexample, XX is 2-fold, 5-fold, 10-fold, 50-fold, 100-fold, or 1000-foldless than YY.

Another aspect is a method of inhibiting metalloenzyme activitycomprising contacting a compound of the formulae herein with ametalloenzyme. In one aspect, the contacting is in vivo. In anotheraspect, the contacting is in vitro.

The method can further be that: wherein the metalloenzyme comprises ametal atom that is iron, zinc, heme iron, manganese, magnesium, ironsulfide cluster, nickel, molybdenum, or copper;

wherein the metalloenzyme is a member of an enzyme class selected fromcytochrome cytochrome P450 family, histone deacetylases, matrixmetalloproteinases, phsophodiesterases, cycloxygenases, carbonicanhydrases, and nitric oxide synthases; the metalloenzyme is aromatase(CYP19), a cyclooxygenase, lanosterol demethylase (CYP51), a nitricoxide synthase, thromboxane synthase (CYP5a), thyroid peroxidase,17-alpha hydroxylase/17,20-lyase (CYP17), aldosterone synthase(CYP11B2), cytochrome P450 2A6, heme oxygenase, indoleamine2,3-dioxygenase, retinoic acid hydroxylase (CYP26), or vitamin Dhydroxylase (CYP24);

wherein the metalloenzyme is 17-alpha hydroxylase/17,20-lyase (CYP17);

wherein the metalloenzyme is 4-hydroxyphenyl pyruvate dioxygenase,5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase,aminopeptidase n, angiotensin converting enzyme, aromatase (CYP19),calcineurin, carbamoyl phosphate synthetase, carbonic anhydrase family,catechol o-methyl transferase, cyclooxygenase family, dihydropyrimidinedehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyltransferase, fumarate reductase, GABA aminotransferase, HIF-prolylhydroxylase, histone deacetylase family, HIV integrase, HIV-1 reversetranscriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51),matrix metalloprotease family, methionine aminopeptidase, neutralendopeptidase, nitric oxide synthase family, phosphodiesterase III,phosphodiesteraseIV, phosphodiesteraseV, pyruvate ferredoxinoxidoreductase, renal peptidase, ribonucleoside diphosphate reductase,thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease,and xanthine oxidase; or

wherein the metalloenzyme is 1-deoxy-d-xylulose-5-phosphatereductoisomerase (DXR), 17-alpha hydroxylase (CYP17), aldosteronesynthase (CYP11B2), aminopeptidase p, anthrax lethal factor, arginase,beta-lactamase, cytochrome P450 2A6, d-ala d-ala ligase, dopaminebeta-hydroxylase, endothelin converting enzyme-1, glutamatecarboxypeptidase II, glutaminyl cyclase, glyoxalase, heme oxygenase,HPV/HSV E1 helicase, indoleamine 2,3-dioxygenase, leukotriene A4hydrolase, methionine aminopeptidase 2, peptide deformylase,phosphodiesteraseVII, relaxase, retinoic acid hydroxylase (CYP26),TNF-alpha converting enzyme (TACE),UDP-(3-O—(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC),vascular adhesion protein-1 (VAP-1), or vitamin D hydroxylase (CYP24).

The methods herein can further comprise administering the compound to asubject.

The methods herein include those herein wherein the compound of formula(I) is identified as having an activity range against CYP17 IC50<0.35 uMand IC50>0.75 μM for CYP2C9, CYP2C19 and CYP3A4; CYP17 IC50<XX μM andIC50>YY μM for CYP2C9, CYP2C19 and CYP3A4, in each instance XX is anindependent number; in each instance YY is an independent number; incertain aspects XX is a number less than YY. In certain aspects, forexample, XX is 2-fold, 5-fold, 10-fold, 50-fold, 100-fold, or 1000-foldless than YY.

The compounds herein include those wherein the compound is identified asattaining affinity, at least in part, for a metalloenzyme by formationof one or more of the following types of chemical interactions or bondsto a metal: sigma bonds, covalent bonds, coordinate-covalent bonds,ionic bonds, pi bonds, delta bonds, or backbonding interactions. Thecompounds can also attain affinity through a weaker interactions withthe metal such as van der Waals interactions, pi cation interactions,pi-anion interactions, dipole-dipole interactions, ion-dipoleinteractions. In one aspect, the compound is identified as having abonding interaction with the metal via the 5-thiazolyl moiety; inanother aspect, the compound is identified as having a bondinginteraction with the metal via the N of the 5-thiazolylmoiety; inanother aspect, the compound is identified as having a bondinginteraction with the metal via the S of the 5-thiazolyl moiety; inanother aspect, the compound is identified as having a bondinginteraction with the metal via the N and S of the 5-thiazolylmoiety.

Methods for assessing metal-ligand binding interactions are known in theart as exemplified in references including, for example, “Principles ofBioinorganic Chemistry” by Lippard and Berg, University Science Books,(1994); “Mechanisms of Inorganic Reactions” by Basolo and Pearson JohnWiley & Sons Inc; 2nd edition (September 1967); “Biological InorganicChemistry” by Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine,University Science Books (2007); Xue et al. “Nature Chemical Biology”,vol. 4, no. 2, 107-109 (2008).

In certain instances, the compounds of the invention are selected fromthe following of Formula (I) (and pharmaceutically acceptable salts,solvates, or hydrates thereof)1-(2-Chloro-thiazol-5-yl)-1-(6,7-dimethoxynaphthalen-2-yl)-2-methylpropan-1-ol  (1);or1-(6,7-dimethoxynaphthalen-2-yl)-2-methyl-1-(thiazol-5-yl)propan-1-ol  (2).

In another aspect, the invention provides a pharmaceutical compositioncomprising the compound of formula I and a pharmaceutically acceptablecarrier.

In other aspects, the invention provides a method of modulatingmetalloenzyme activity in a subject, comprising contacting the subjectwith a compound of formula I, in an amount and under conditionssufficient to modulate metalloenzyme activity.

In one aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-related disorder ordisease, comprising administering to the subject an effective amount ofa compound or pharmaceutical composition of formula I.

In another aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-related disorder ordisease, wherein the subject has been identified as in need of treatmentfor a metalloenzyme-related disorder or disease, comprisingadministering to said subject in need thereof, an effective amount of acompound or pharmaceutical composition of formula I, such that saidsubject is treated for said disorder.

In another aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-mediated disorder ordisease, wherein the subject has been identified as in need of treatmentfor a metalloenzyme-mediated disorder or disease, comprisingadministering to said subject in need thereof, an effective amount of acompound or pharmaceutical composition of formula I, such thatmetalloenzyme activity in said subject is modulated (e.g., downregulated, inhibited). In another aspect, the compounds delineatedherein preferentially target cancer cells over nontransformed cells.

The methods herein include those wherein the disease or disorder ismediated by any of 4-hydroxyphenyl pyruvate dioxygenase, 5-lipoxygenase,adenosine deaminase, alcohol dehydrogenase, aminopeptidase n,angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamoylphosphate synthetase, carbonic anhydrase family, catechol o-methyltransferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1,DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase,fumarate reductase, GABA aminotransferase, HIF-prolyl hydroxylase,histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase,isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrixmetalloprotease family, methionine aminopeptidase, neutralendopeptidase, nitric oxide synthase family, phosphodiesterase III,phosphodiesteraseIV, phosphodiesteraseV, pyruvate ferredoxinoxidoreductase, renal peptidase, ribonucleoside diphosphate reductase,thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, orxanthine oxidase.

The methods herein include those wherein the disease or disorder ismediated by any of 1-deoxy-d-xylulose-5-phosphate reductoisomerase(DXR), 17-alpha hydroxylase (CYP17), aldosterone synthase (CYP11B2),aminopeptidase p, anthrax lethal factor, arginase, beta-lactamase,cytochrome P450 2A6, d-ala d-ala ligase, dopamine beta-hydroxylase,endothelin converting enzyme-1, glutamate carboxypeptidase II,glutaminyl cyclase, glyoxalase, heme oxygenase, HPV/HSV E1 helicase,indoleamine 2,3-dioxygenase, leukotriene A4 hydrolase, methionineaminopeptidase 2, peptide deformylase, phosphodiesteraseVII, relaxase,retinoic acid hydroxylase (CYP26), TNF-alpha converting enzyme (TACE),UDP-(3-O—(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC),vascular adhesion protein-1 (VAP-1), or vitamin D hydroxylase (CYP24).

The methods herein include those wherein the disease or disorder iscancer, cardiovascular disease, inflammatory disease, infectiousdisease, metabolic disease, opthalmologic disease, central nervoussystem (CNS) disease, urologic disease, or gastrointestinal disease.

The methods herein include those wherein the disease or disorder isprostate cancer, breast cancer, inflammatory bowel disease, psoriasis,systemic fungal infection, skin structure fungal infection, mucosalfungal infection, or onychomycosis. prostate hypertrophy, testicularcancer, virilism, hirsutism, male pattern alopecia, precocious puberty,uterine cancer, ovarian cancer, mastopathy, uterine myoma, uterineadenomyosis, or polycystic ovarian syndrome.

Methods delineated herein include those wherein the subject isidentified as in need of a particular stated treatment. Identifying asubject in need of such treatment can be in the judgment of a subject ora health care professional and can be subjective (e.g. opinion) orobjective (e.g. measurable by a test or diagnostic method).

Another aspect of the invention is a composition comprising a compounddelineated herein (e.g., a compound of formula (I)) and anagriculturally acceptable carrier.

Another aspect of the invention is a method of treating or preventing ametalloenzyme-mediated disease or disorder in a plant comprisingcontacting a compound herein with the plant.

Another aspect of the invention is a method of inhibiting metalloenzymeactivity in a plant comprising contacting a compound herein with theplant.

DETAILED DESCRIPTION Definitions

In order that the invention may be more readily understood, certainterms are first defined here for convenience.

As used herein, the term “treating” a disorder encompasses preventing,ameliorating, mitigating and/or managing the disorder and/or conditionsthat may cause the disorder. The terms “treating” and “treatment” referto a method of alleviating or abating a disease and/or its attendantsymptoms. In accordance with the present invention “treating” includespreventing, blocking, inhibiting, attenuating, protecting against,modulating, reversing the effects of and reducing the occurrence ofe.g., the harmful effects of a disorder.

As used herein, “inhibiting” encompasses preventing, reducing andhalting progression. Note that “enzyme inhibition” (e.g., metalloenzymeinhibition) is distinguished and described below.

The term “modulate” refers to increases or decreases in the activity ofan enzyme in response to exposure to a compound of the invention.

The terms “isolated,” “purified,” or “biologically pure” refer tomaterial that is substantially or essentially free from components thatnormally accompany it as found in its native state. Purity andhomogeneity are typically determined using analytical chemistrytechniques such as polyacrylamide gel electrophoresis or highperformance liquid chromatography. Particularly, in embodiments thecompound is at least 85% pure, more preferably at least 90% pure, morepreferably at least 95% pure, and most preferably at least 99% pure.

The term “administration” or “administering” includes routes ofintroducing the compound(s) to a subject to perform their intendedfunction. Examples of routes of administration which can be used includeinjection (subcutaneous, intravenous, parenterally, intraperitoneally,intrathecal), topical, oral, inhalation, rectal and transdermal.

The term “effective amount” includes an amount effective, at dosages andfor periods of time necessary, to achieve the desired result. Aneffective amount of compound may vary according to factors such as thedisease state, age, and weight of the subject, and the ability of thecompound to elicit a desired response in the subject. Dosage regimensmay be adjusted to provide the optimum therapeutic response. Aneffective amount is also one in which any toxic or detrimental effects(e.g., side effects) of the inhibitor compound are outweighed by thetherapeutically beneficial effects.

The phrases “systemic administration,” “administered systemically”,“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound(s), drug or other material,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The term “therapeutically effective amount” refers to that amount of thecompound being administered sufficient to prevent development of oralleviate to some extent one or more of the symptoms of the condition ordisorder being treated.

A therapeutically effective amount of compound (i.e., an effectivedosage) may range from about 0.005 μg/kg to about 200 mg/kg, preferablyabout 0.01 mg/kg to about 200 mg/kg, more preferably about 0.015 mg/kgto about 30 mg/kg of body weight. In other embodiments, thetherapeutically effect amount may range from about 1.0 pM to about 10μM. The skilled artisan will appreciate that certain factors mayinfluence the dosage required to effectively treat a subject, includingbut not limited to the severity of the disease or disorder, previoustreatments, the general health and/or age of the subject, and otherdiseases present. Moreover, treatment of a subject with atherapeutically effective amount of a compound can include a singletreatment or, preferably, can include a series of treatments. In oneexample, a subject is treated with a compound in the range of betweenabout 0.005 μg/kg to about 200 mg/kg of body weight, one time per dayfor between about 1 to 10 weeks, preferably between 2 to 8 weeks, morepreferably between about 3 to 7 weeks, and even more preferably forabout 4, 5, or 6 weeks. In another example, a subject may be treateddaily for several years in the setting of a chronic condition orillness. It will also be appreciated that the effective dosage of acompound used for treatment may increase or decrease over the course ofa particular treatment.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “diastereomers” refers to stereoisomers with two or morecenters of dissymmetry and whose molecules are not mirror images of oneanother.

The term “enantiomers” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another. An equimolarmixture of two enantiomers is called a “racemic mixture” or a“racemate.”

The term “isomers” or “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

The term “prodrug” includes compounds with moieties which can bemetabolized in vivo. Generally, the prodrugs are metabolized in vivo byesterases or by other mechanisms to active drugs. Examples of prodrugsand their uses are well known in the art (See, e.g., Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The prodrugs can beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form or hydroxyl with a suitable esterifying agent. Hydroxyl groupscan be converted into esters via treatment with a carboxylic acid.Examples of prodrug moieties include substituted and unsubstituted,branch or unbranched lower alkyl ester moieties, (e.g., propionoic acidesters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters(e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g.,acetyloxymethyl ester), acyloxy lower alkyl esters (e.g.,pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkylesters (e.g., benzyl ester), substituted (e.g., with methyl, halo, ormethoxy substituents) aryl and aryl-lower alkyl esters, amides,lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferredprodrug moieties are propionoic acid esters and acyl esters. Prodrugswhich are converted to active forms through other mechanisms in vivo arealso included. In aspects, the compounds of the invention are prodrugsof any of the formulae herein.

The term “subject” refers to animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In certain embodiments, thesubject is a human.

The terms “a,” “an,” and “the” refer to “one or more” when used in thisapplication, including the claims. Thus, for example, reference to “asample” includes a plurality of samples, unless the context clearly isto the contrary (e.g., a plurality of samples), and so forth.

Throughout this specification and the claims, the words “comprise,”“comprises,” and “comprising” are used in a non-exclusive sense, exceptwhere the context requires otherwise.

As used herein, the term “about,” when referring to a value is meant toencompass variations of, in some embodiments ±20%, in some embodiments±10%, in some embodiments ±5%, in some embodiments ±1%, in someembodiments ±0.5%, and in some embodiments ±0.1% from the specifiedamount, as such variations are appropriate to perform the disclosedmethods or employ the disclosed compositions.

Use of the word “inhibitor” herein is meant to mean a molecule thatexhibits activity for inhibiting a metalloenzyme. By “inhibit” herein ismeant to decrease the activity of metalloenzyme, as compared to theactivity of metalloenzyme in the absence of the inhibitor. In someembodiments, the term “inhibit” means a decrease in metalloenzymeactivity of at least about 5%, at least about 10%, at least about 20%,at least about 25%, at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, or at least about95%. In other embodiments, inhibit means a decrease in metalloenzymeactivity of about 5% to about 25%, about 25% to about 50%, about 50% toabout 75%, or about 75% to 100%. In some embodiments, inhibit means adecrease in metalloenzyme activity of about 95% to 100%, e.g., adecrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreasescan be measured using a variety of techniques that would be recognizableby one of skill in the art. Particular assays for measuring individualactivity are described below.

Furthermore the compounds of the invention include olefins having eithergeometry: “Z” refers to what is referred to as a “cis” (same side)configuration whereas “E” refers to what is referred to as a “trans”(opposite side) configuration. With respect to the nomenclature of achiral center, the terms “d” and “1” configuration are as defined by theIUPAC Recommendations. As to the use of the terms, diastereomer,racemate, epimer and enantiomer, these will be used in their normalcontext to describe the stereochemistry of preparations.

As used herein, the term “alkyl” refers to a straight-chained orbranched hydrocarbon group containing 1 to 12 carbon atoms. The term“lower alkyl” refers to a C1-C6 alkyl chain. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl.Alkyl groups may be optionally substituted with one or moresubstituents.

The term “alkenyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing 2 to 12 carbon atomsand at least one carbon-carbon double bond. Alkenyl groups may beoptionally substituted with one or more substituents.

The term “alkynyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing the 2 to 12 carbonatoms and at least one carbon-carbon triple bond. Alkynyl groups may beoptionally substituted with one or more substituents.

The sp² or sp carbons of an alkenyl group and an alkynyl group,respectively, may optionally be the point of attachment of the alkenylor alkynyl groups.

The term “alkoxy” refers to an —O-alkyl radical.

As used herein, the term “halogen”, “hal” or “halo” means —F, —Cl, —Bror —I.

The term “haloalkoxy” refers to an —O-alkyl radical that is substitutedby one or more halo substituents. Examples of haloalkoxy groups includetrifluoromethoxy, and 2,2,2-trifluoroethoxy.

The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or7-14 membered bicyclic ring system having at least one saturated ring orhaving at least one non-aromatic ring, wherein the non-aromatic ring mayhave some degree of unsaturation. Cycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a cycloalkyl group may be substituted by asubstituent. Representative examples of cycloalkyl group includecyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and thelike.

The term “aryl” refers to a hydrocarbon monocyclic, bicyclic ortricyclic aromatic ring system. Aryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by asubstituent. Examples of aryl groups include phenyl, naphthyl,anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andthe remainder ring atoms being carbon (with appropriate hydrogen atomsunless otherwise indicated). Heteroaryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heteroaryl group may be substituted by asubstituent. Examples of heteroaryl groups include pyridyl, furanyl,thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl,isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and thelike.

The term “nitrogen-containing heteroaryl” refers to a heteroaryl grouphaving 1-4 ring nitrogen heteroatoms if monocyclic, 1-6 ring nitrogenheteroatoms if bicyclic, or 1-9 ring nitrogen heteroatoms if tricyclic.

The term “heterocycloalkyl” refers to a nonaromatic 3-8 memberedmonocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ringsystem comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, S, B, P or Si, wherein the nonaromatic ring system iscompletely saturated. Heterocycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heterocycloalkyl group may besubstituted by a substituent. Representative heterocycloalkyl groupsinclude piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl,thiirenyl, and the like.

The term “alkylamino” refers to an amino substituent which is furthersubstituted with one or two alkyl groups. The term “aminoalkyl” refersto an alkyl substituent which is further substituted with one or moreamino groups. The term “hydroxyalkyl” or “hydroxylalkyl” refers to analkyl substituent which is further substituted with one or more hydroxylgroups. The alkyl or aryl portion of alkylamino, aminoalkyl,mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl,sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionallysubstituted with one or more substituents.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

Alkylating agents are any reagent that is capable of effecting thealkylation of the functional group at issue (e.g., oxygen atom of analcohol, nitrogen atom of an amino group). Alkylating agents are knownin the art, including in the references cited herein, and include alkylhalides (e.g., methyl iodide, benzyl bromide or chloride), alkylsulfates (e.g., methyl sulfate), or other alkyl group-leaving groupcombinations known in the art. Leaving groups are any stable speciesthat can detach from a molecule during a reaction (e.g., eliminationreaction, substitution reaction) and are known in the art, including inthe references cited herein, and include halides (e.g., I—, Cl—, Br—,F—), hydroxy, alkoxy (e.g., —OMe, —O-t-Bu), acyloxy anions (e.g., —OAc,—OC(O)CF₃), sulfonates (e.g., mesyl, tosyl), acetamides (e.g.,—NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g.,—OP(O)(OEt)₂), water or alcohols (protic conditions), and the like.

In certain embodiments, substituents on any group (such as, for example,alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, heterocycloalkyl) can be at any atom of that group, whereinany group that can be substituted (such as, for example, alkyl, alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,heterocycloalkyl) can be optionally substituted with one or moresubstituents (which may be the same or different), each replacing ahydrogen atom. Examples of suitable substituents include, but are notlimited to alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano,nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl),carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl,thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl,dialkylamino, alkylcarbonylamino, alkylaminocarbonyl,alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl,or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl,amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, imino, carbamido, carbamyl,thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl,mercaptoalkoxy, N-hydroxyamidinyl, or N′-aryl, N″-hydroxyamidinyl.

Compounds of the invention can be made by means known in the art oforganic synthesis. Methods for optimizing reaction conditions, ifnecessary minimizing competing by-products, are known in the art.Reaction optimization and scale-up may advantageously utilize high-speedparallel synthesis equipment and computer-controlled microreactors (e.g.Design And Optimization in Organic Synthesis, 2^(nd) Edition, Carlson R,Ed, 2005; Elsevier Science Ltd; Jähnisch, K et al, Angew. Chem. Int. Ed.Engl. 2004 43: 406; and references therein). Additional reaction schemesand protocols may be determined by the skilled artesian by use ofcommercially available structure-searchable database software, forinstance, SciFinder® (CAS division of the American Chemical Society) andCrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searchingusing an internet search engine such as Google® or keyword databasessuch as the US Patent and Trademark Office text database.

The compounds herein may also contain linkages (e.g., carbon-carbonbonds) wherein bond rotation is restricted about that particularlinkage, e.g. restriction resulting from the presence of a ring ordouble bond. Accordingly, all cis/trans and E/Z isomers are expresslyincluded in the present invention. The compounds herein may also berepresented in multiple tautomeric forms, in such instances, theinvention expressly includes all tautomeric forms of the compoundsdescribed herein, even though only a single tautomeric form may berepresented. All such isomeric forms of such compounds herein areexpressly included in the present invention. All crystal forms andpolymorphs of the compounds described herein are expressly included inthe present invention. Also embodied are extracts and fractionscomprising compounds of the invention. The term isomers is intended toinclude diastereoisomers, enantiomers, regioisomers, structural isomers,rotational isomers, tautomers, and the like. For compounds which containone or more stereogenic centers, e.g., chiral compounds, the methods ofthe invention may be carried out with an enantiomerically enrichedcompound, a racemate, or a mixture of diastereomers.

Preferred enantiomerically enriched compounds have an enantiomericexcess of 50% or more, more preferably the compound has an enantiomericexcess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more. In preferredembodiments, only one enantiomer or diastereomer of a chiral compound ofthe invention is administered to cells or a subject.

Methods of Treatment

In one aspect, the invention provides a method of modulating themetalloenzyme activity of a cell in a subject, comprising contacting thesubject with a compound of formula I, in an amount and under conditionssufficient to modulate metalloenzyme activity.

In one embodiment, the modulation is inhibition.

In another aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-mediated disorder ordisease, comprising administering to the subject an effective amount ofa compound or pharmaceutical composition of formula I.

In other aspects, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-mediated disorder ordisease, wherein the subject has been identified as in need of treatmentfor a metalloenzyme-mediated disorder or disease, comprisingadministering to said subject in need thereof, an effective amount of acompound or pharmaceutical composition of formula I, such that saidsubject is treated for said disorder.

In certain embodiments, the invention provides a method of treating adisease, disorder or symptom thereof, wherein the disorder is cancer,cardiovascular disease, inflammatory disease or infectious disease. Inother embodiments the disease, disorder or symptom thereof is metabolicdisease, opthalmologic disease, central nervous system (CNS) disease,urologic disease, or gastrointestinal disease. In certain embodimentsthe disease is prostate cancer, breast cancer, inflammatory boweldisease, psoriasis, systemic fungal infection, skin structure fungalinfection, mucosal fungal infection, and onychomycosis. In other aspectsthe disease is prostate hypertrophy, testicular cancer, virilism,hirsutism, male pattern alopecia, precocious puberty, uterine cancer,ovarian cancer, mastopathy, uterine myoma, endometriosis, uterineadenomyosis, or polycystic ovarian syndrome.

In certain embodiments, the subject is a mammal, preferably a primate orhuman.

In another embodiment, the invention provides a method as describedabove, wherein the effective amount of the compound of formula I is asdescribed above.

In another embodiment, the invention provides a method as describedabove, wherein the compound of formula I is administered intravenously,intramuscularly, subcutaneously, intracerebroventricularly, orally ortopically.

In other embodiments, the invention provides a method as describedabove, wherein the compound of formula I is administered alone or incombination with one or more other therapeutics. In a furtherembodiment, the additional therapeutic agent is an anti-cancer agent,antifungal agent, cardiovascular agent, antiinflammatory agent,chemotherapeutic agent, an anti-angiogenesis agent, cytotoxic agent, ananti-proliferation agent, metabolic disease agent, opthalmologic diseaseagent, central nervous system (CNS) disease agent, urologic diseaseagent, or gastrointestinal disease agent.

Another object of the present invention is the use of a compound asdescribed herein (e.g., of any formulae herein) in the manufacture of amedicament for use in the treatment of a metalloenzyme-mediated disorderor disease. Another object of the present invention is the use of acompound as described herein (e.g., of any formulae herein) for use inthe treatment of a metalloenzyme-mediated disorder or disease. Anotherobject of the present invention is the use of a compound as describedherein (e.g., of any formulae herein) in the manufacture of anagricultural composition for use in the treatment or prevention of ametalloenzyme-mediated disorder or disease in agricultrual or agrariansettings.

Pharmaceutical Compositions

In one aspect, the invention provides a pharmaceutical compositioncomprising the compound of formula I and a pharmaceutically acceptablecarrier.

In another embodiment, the invention provides a pharmaceuticalcomposition further comprising an additional therapeutic agent. In afurther embodiment, the additional therapeutic agent is an anti-canceragent, antifungal agent, cardiovascular agent, antiinflammatory agent,chemotherapeutic agent, an anti-angiogenesis agent, cytotoxic agent, ananti-proliferation agent, metabolic disease agent, opthalmologic diseaseagent, central nervous system (CNS) disease agent, urologic diseaseagent, or gastrointestinal disease agent.

In one aspect, the invention provides a kit comprising an effectiveamount of a compound of formula I, in unit dosage form, together withinstructions for administering the compound to a subject suffering fromor susceptible to a metalloenzyme-mediated disease or disorder,including cancer, solid tumor, cardiovascular disease, inflammatorydisease, infectious disease. In other embodiments the disease, disorderor symptom thereof is metabolic disease, opthalmologic disease, centralnervous system (CNS) disease, urologic disease, or gastrointestinaldisease.

The term “pharmaceutically acceptable salts” or “pharmaceuticallyacceptable carrier” is meant to include salts of the active compoundswhich are prepared with relatively nontoxic acids or bases, depending onthe particular substituents found on the compounds described herein.When compounds of the present invention contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredbase, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, or magnesium salt, or asimilar salt. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, e.g., Berge et al.,Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts. Other pharmaceutically acceptable carriersknown to those of skill in the art are suitable for the presentinvention.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

The invention also provides a pharmaceutical composition, comprising aneffective amount a compound described herein and a pharmaceuticallyacceptable carrier. In an embodiment, compound is administered to thesubject using a pharmaceutically-acceptable formulation, e.g., apharmaceutically-acceptable formulation that provides sustained deliveryof the compound to a subject for at least 12 hours, 24 hours, 36 hours,48 hours, one week, two weeks, three weeks, or four weeks after thepharmaceutically-acceptable formulation is administered to the subject.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of this invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient, composition, and mode of administration, without being toxic(or unacceptably toxic) to the patient.

In use, at least one compound according to the present invention isadministered in a pharmaceutically effective amount to a subject in needthereof in a pharmaceutical carrier by intravenous, intramuscular,subcutaneous, or intracerebro ventricular injection or by oraladministration or topical application. In accordance with the presentinvention, a compound of the invention may be administered alone or inconjunction with a second, different therapeutic. By “in conjunctionwith” is meant together, substantially simultaneously or sequentially.In one embodiment, a compound of the invention is administered acutely.The compound of the invention may therefore be administered for a shortcourse of treatment, such as for about 1 day to about 1 week. In anotherembodiment, the compound of the invention may be administered over alonger period of time to ameliorate chronic disorders, such as, forexample, for about one week to several months depending upon thecondition to be treated.

By “pharmaceutically effective amount” as used herein is meant an amountof a compound of the invention, high enough to significantly positivelymodify the condition to be treated but low enough to avoid serious sideeffects (at a reasonable benefit/risk ratio), within the scope of soundmedical judgment. A pharmaceutically effective amount of a compound ofthe invention will vary with the particular goal to be achieved, the ageand physical condition of the patient being treated, the severity of theunderlying disease, the duration of treatment, the nature of concurrenttherapy and the specific compound employed. For example, atherapeutically effective amount of a compound of the inventionadministered to a child or a neonate will be reduced proportionately inaccordance with sound medical judgment. The effective amount of acompound of the invention will thus be the minimum amount which willprovide the desired effect.

A decided practical advantage of the present invention is that thecompound may be administered in a convenient manner such as byintravenous, intramuscular, subcutaneous, oral orintra-cerebroventricular injection routes or by topical application,such as in creams or gels. Depending on the route of administration, theactive ingredients which comprise a compound of the invention may berequired to be coated in a material to protect the compound from theaction of enzymes, acids and other natural conditions which mayinactivate the compound. In order to administer a compound of theinvention by other than parenteral administration, the compound can becoated by, or administered with, a material to prevent inactivation.

The compound may be administered parenterally or intraperitoneally.Dispersions can also be prepared, for example, in glycerol, liquidpolyethylene glycols, and mixtures thereof, and in oils.

Some examples of substances which can serve as pharmaceutical carriersare sugars, such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethycellulose, ethylcellulose and cellulose acetates; powderedtragancanth; malt; gelatin; talc; stearic acids; magnesium stearate;calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil,sesame oil, olive oil, corn oil and oil of theobroma; polyols such aspropylene glycol, glycerine, sorbitol, manitol, and polyethylene glycol;agar; alginic acids; pyrogen-free water; isotonic saline; and phosphatebuffer solution; skim milk powder; as well as other non-toxic compatiblesubstances used in pharmaceutical formulations such as Vitamin C,estrogen and echinacea, for example. Wetting agents and lubricants suchas sodium lauryl sulfate, as well as coloring agents, flavoring agents,lubricants, excipients, tableting agents, stabilizers, anti-oxidants andpreservatives, can also be present. Solubilizing agents, including forexample, cremaphore and beta-cyclodextrins can also used in thepharmaceutical compositions herein.

Pharmaceutical compositions comprising the active compounds of thepresently disclosed subject matter (or prodrugs thereof) can bemanufactured by means of conventional mixing, dissolving, granulating,dragee-making levigating, emulsifying, encapsulating, entrapping orlyophilization processes. The compositions can be formulated inconventional manner using one or more physiologically acceptablecarriers, diluents, excipients or auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically.

Pharmaceutical compositions of the presently disclosed subject mattercan take a form suitable for virtually any mode of administration,including, for example, topical, ocular, oral, buccal, systemic, nasal,injection, transdermal, rectal, vaginal, and the like, or a formsuitable for administration by inhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) can beformulated as solutions, gels, ointments, creams, suspensions, and thelike.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal, oral, or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions also can contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection canbe presented in unit dosage form (e.g., in ampules or in multidosecontainers) and can contain added preservatives.

Alternatively, the injectable formulation can be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, and the like,before use. To this end, the active compound(s) can be dried by anyart-known technique, such as lyophilization, and reconstituted prior touse.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions can take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets can be coated by methods well known in theart with, for example, sugars or enteric coatings.

Liquid preparations for oral administration can take the form of, forexample, elixirs, solutions, syrups or suspensions, or they can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol or fractionated vegetable oils); and preservatives (e.g., methylor propyl p-hydroxybenzoates or sorbic acid). The preparations also cancontain buffer salts, preservatives, flavoring, coloring and sweeteningagents as appropriate.

Preparations for oral administration can be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in a conventional manner.

For rectal and vaginal routes of administration, the active compound(s)can be formulated as solutions (for retention enemas), suppositories, orointments containing conventional suppository bases, such as cocoabutter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit canbe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5-20mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH5 to pH7, with a pH of about pH 5.5 being typical.

For ocular administration, the active compound(s) or prodrug(s) can beformulated as a solution, emulsion, suspension, and the like, suitablefor administration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. No. 6,261,547; U.S.Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807;U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No.5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat.No. 4,882,150; and U.S. Pat. No. 4,738,851, each of which isincorporated herein by reference in its entirety.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient can be formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptioncan be used. To this end, permeation enhancers can be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat.No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168; U.S.Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No. 5,164,189;U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat. No.5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475, each ofwhich is incorporated herein by reference in its entirety.

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat can be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) also can be employed.

The pharmaceutical compositions can, if desired, be presented in a packor dispenser device which can contain one or more unit dosage formscontaining the active compound(s). The pack can, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice can be accompanied by instructions for administration.

The active compound(s) or prodrug(s) of the presently disclosed subjectmatter, or compositions thereof, will generally be used in an amounteffective to achieve the intended result, for example in an amounteffective to treat or prevent the particular disease being treated. Thecompound(s) can be administered therapeutically to achieve therapeuticbenefit or prophylactically to achieve prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying disorder suchthat the patient reports an improvement in feeling or condition,notwithstanding that the patient can still be afflicted with theunderlying disorder. For example, administration of a compound to apatient suffering from an allergy provides therapeutic benefit not onlywhen the underlying allergic response is eradicated or ameliorated, butalso when the patient reports a decrease in the severity or duration ofthe symptoms associated with the allergy following exposure to theallergen. As another example, therapeutic benefit in the context ofasthma includes an improvement in respiration following the onset of anasthmatic attack, or a reduction in the frequency or severity ofasthmatic episodes. Therapeutic benefit also includes halting or slowingthe progression of the disease, regardless of whether improvement isrealized.

For prophylactic administration, the compound can be administered to apatient at risk of developing one of the previously described diseases.A patient at risk of developing a disease can be a patient havingcharacteristics placing the patient in a designated group of at riskpatients, as defined by an appropriate medical professional or group. Apatient at risk may also be a patient that is commonly or routinely in asetting where development of the underlying disease that may be treatedby administration of a metalloenzyme inhibitor according to theinvention could occur. In other words, the at risk patient is one who iscommonly or routinely exposed to the disease or illness causingconditions or may be acutely exposed for a limited time. Alternatively,prophylactic administration can be applied to avoid the onset ofsymptoms in a patient diagnosed with the underlying disorder.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, and the like. Determination of aneffective dosage is well within the capabilities of those skilled in theart.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC50 of the particular compound as measured in asin vitro assay, such as the in vitro fungal MIC or MFC and other invitro assays described in the Examples section. Calculating dosages toachieve such circulating blood or serum concentrations taking intoaccount the bioavailability of the particular compound is well withinthe capabilities of skilled artisans. For guidance, see Fingl &Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein, which areincorporated herein by reference.

Initial dosages also can be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but can be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration, and variousfactors discussed above. Dosage amount and interval can be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. In cases oflocal administration or selective uptake, such as local topicaladministration, the effective local concentration of active compound(s)cannot be related to plasma concentration. Skilled artisans will be ableto optimize effective local dosages without undue experimentation.

The compound(s) can be administered once per day, a few or several timesper day, or even multiple times per day, depending upon, among otherthings, the indication being treated and the judgment of the prescribingphysician.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) can be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Therecitation of an embodiment herein includes that embodiment as anysingle embodiment or in combination with any other embodiments orportions thereof.

Agricultural Applications

The compounds and compositions herein can be used in methods ofmodulating metalloenzyme activity in a microorganism on a plantcomprising contacting a compound herein with the plant (e.g., seed,seedling, grass, weed, grain). The compounds and compositions herein canbe used to treat a plant, field or other agricultural area (e.g., asherbicides, pesticides, growth regulators, etc.) by administering thecompound or composition (e.g., contacting, applying, spraying,atomizing, dusting, etc.) to the subject plant, field or otheragricultural area. The administration can be either pre- orpost-emergence. The administration can be either as a treatment orpreventative regimen.

One aspect is a method of treating or preventing a fungal disease ordisorder in or on a plant comprising contacting a compound of any of theformulae herein with the plant. Another aspect is a method of treatingor preventing fungi growth in or on a plant comprising contacting acompound of any of the formulae herein with the plant. Another aspect isa method of inhibiting microorganisms in or on a plant comprisingcontacting a compound of any of the formulae herein with the plant.

The compositions comprising compounds herein can be employed, forexample, in the form of directly sprayable aqueous solutions, powders,suspensions, also highly-concentrated aqueous, oily or other suspensionsor dispersions, emulsions, oil dispersions, pastes, dusts, materials forspreading or granules, by means of spraying, atomizing, dusting,spreading or pouring.

Aqueous use forms can be prepared from emulsion concentrates,suspensions, pastes, wettable powders or water-dispersible granules byadding water. To prepare emulsions, pastes or oil dispersions, thesubstances, as such or dissolved in an oil or solvent, can behomogenized in water by means of wetting agent, tackifier, dispersant oremulsifier. However, it is also possible to prepare concentratescomposed of active substance, wetting agent, tackifier, dispersant oremulsifier and, if appropriate, solvent or oil, and these concentratesare suitable for dilution with water.

Granules, e.g. coated granules, impregnated granules and homogeneousgranules, can be prepared by binding the active ingredients (e.g.,compounds herein) to solid carriers. Solid carriers are mineral earthssuch as silicas, silica gels, silicates, talc, kaolin, limestone, lime,chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate,magnesium sulfate, magnesium oxide, ground synthetic material,fertilizers such as ammonium sulfate, ammonium phosphate, ammoniumnitrate, ureas and products of vegetable origin such as cereal meal,tree bark meal, wood meal and nutshell meal, cellulose powders or othersolid carriers.

The compounds herein can be formulated as ordinary tablets, capsules,solids, liquids, emulsions, slurries, oils, fine granules or powders,which are suitable for administration to plants, fields or otheragricultural areas. In preferred embodiments, the preparation includesbetween 1 and 95% (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 25%, 75%, 80%,90%, 95%) compound herein in a carrier or diluent. The compositionsdelineated herein include the compounds of the formulae delineatedherein, as well as additional agricultural agents if present, in amountseffective for controlling (e.g., modulating, inhibiting) ametalloenzyme-mediated agricultural disease or disorder.

In one approach, a compound herein is provided in an encapsulatedformulation (liquid or powder). Specific materials suitable for use incapsule materials include, but are not limited to, porous particulatesor substrates such as silica, perlite, talc, clay, pyrophyllite,diatomaceous earth, gelatin and gels, polymers (e.g., polyurea,polyurethane, polyamide, polyester, etc.), polymeric particles, orcellulose. These include, for example, hollow fibers, hollow tubes ortubing which release a compound specified herein through the walls,capillary tubing which releases the compound out of an opening in thetubing, polymeric blocks of different shapes, e.g., strips, blocks,tablets, discs, which release the compound out of the polymer matrix,membrane systems which hold the compound within an impermeable containerand release it through a measured permeable membrane, and combinationsof the foregoing. Examples of such dispensing compositions are polymerlaminates, polyvinyl chloride pellets, and microcapillaries.

Encapsulation processes are typically classified as chemical ormechanical. Examples of chemical processes for encapsulation include,but are not limited to, complex coacervation, polymer-polymerincompatibility, interfacial polymerization in liquid media, in situpolymerization, in-liquid drying, thermal and ionic gelation in liquidmedia, desolvation in liquid media, starch-based chemistry processes,trapping in cyclodextrins, and formation of liposomes. Examples ofmechanical processes for encapsulation include, but are not limited to,spray drying, spray chilling, fluidized bed, electrostatic deposition,centrifugal extrusion, spinning disk or rotational suspensionseparation, annular-jet encapsulation, polymerization at liquid-gas orsolid-gas interface, solvent evaporation, pressure extrusion or sprayinginto solvent extraction bath.

Microcapsules are also suitable for the long-term release of activecompound herein. Microcapsules are small particles that contain a corematerial or active ingredient surrounded by a coating or shell. The sizeof the microcapsule typically varies from 1 to 1000 microns withcapsules smaller than 1 micron classified as nanocapsules and capsuleslarger than 1000 microns as macrocapsules. Core payload usually variesfrom 0.1 to 98 weight percent. Microcapsules can have a variety ofstructures (continuous core/shell, multinuclear, or monolithic) and haveirregular or geometric shapes.

In another approach, the compound herein is provided in an oil-baseddelivery system. Oil release substrates include vegetable and/or mineraloils. In one embodiment, the substrate also contains a surface activeagent that renders the composition readily dispersable in water; suchagents include wetting agents, emulsifying agents, dispersing agents,and the like.

Compounds of the invention can also be provided as emulsions. Emulsionformulations can be found as water in oil (w/o) or oil in water (o/w).Droplet size can vary from the nanometer scale (colloidal dispersion) toseveral hundred microns. A variety of surfactants and thickeners areusually incorporated in the formulation to modify the size of thedroplets, stabilize the emulsion, and modify the release.

Alternatively, compounds of the invention may also be formulated in asolid tablet and comprise (and preferably consist essentially of) anoil, a protein/carbohydrate material (preferably vegetable based), asweetener and an active ingredient useful in the prevention or treatmentof a metalloenzyme-mediated agricultural disease or disorder. In oneembodiment the invention provides a solid tablet and comprises (andpreferably consist essentially of) an oil, a protein/carbohydratematerial (preferably vegetable based), a sweetener and an activeingredient (e.g., compound herein or combinations or derivativesthereof) useful in the prevention or treatment a metalloenzyme-mediatedagricultural disease or disorder. Tablets typically contain about 4-40%(e.g., 5%, 10%, 20%, 30%, 40%) by weight of an oil (e.g., plant oil,such as corn, sunflower, peanut, olive, grape seed, tung, turnip,soybean, cotton seed, walnut, palm, castor, earth almond, hazelnut,avocado, sesame, croton tiglium, cacao, linseed, rape-seed, and canolaoils and their hydrogenated derivatives; petroleum derived oils (e.g.,parafins and petroleum jelly), and other water immiscible hydrocarbons(e.g., parafins). The tablets further contain from about 5-40% (e.g.,5%, 10%, 20%, 30%, 40%) by weight of a vegetable-basedprotein/carbohydrate material. The material contains both a carbohydrateportion (e.g., derived from cereal grains, such as wheat, rye, barley,oat, corn, rice, millet, sorghum, birdseed, buckwheat, alfalfa, mielga,corn meal, soybean meal, grain flour, wheat middlings, wheat bran, corngluten meal, algae meal, dried yeast, beans, rice) and a proteinportion.

Optionally, various excipients and binders can be used in order toassist with delivery of the active ingredient or to provide theappropriate structure to the tablet. Preferred excipients and bindersinclude anhydrous lactose, microcrystalline cellulose, corn starch,magnesium estearate, calcium estearate, zinc estearate, sodiccarboxymethylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose,and mixtures thereof.

The invention provides kits for the treatment or prevention ofagricultural or plant disease or disorders. In one embodiment, the kitincludes a composition containing an effective amount of a compoundherein in a form suitable for delivery to a site plant. In someembodiments, the kit comprises a container which contains a compound offormula (I); such containers can be boxes, ampules, bottles, vials,tubes, bags, pouches, blister-packs, or other suitable container formsknown in the art. Such containers can be made of plastic, glass,laminated paper, metal foil, or other materials suitable for holdingcompounds.

If desired the compound(s) of the invention is provided together withinstructions for administering it to a plant, field, or otheragricultural area. The instructions will generally include informationabout the use of the composition for the treatment or prevention of ametalloenzyme-mediated agricultural disease or disorder. In otherembodiments, the instructions include at least one of the following:description of the compound; dosage schedule and administration fortreatment or prevention of a metalloenzyme-mediated agricultural diseaseor disorder; precautions; warnings; description of research studies;and/or references. The instructions may be printed directly on thecontainer (when present), or as a label applied to the container, or asa separate sheet, pamphlet, card, or folder supplied in or with thecontainer.

EXAMPLES

The present invention will now be demonstrated using specific examplesthat are not to be construed as limiting.

General Experimental Procedures

Definitions of variables in the structures in schemes herein arecommensurate with those of corresponding positions in the formulaedelineated herein.

Synthesis of 5-Thiazoles

Syntheses of 5-thiazole targets (I) may be accomplished using theschemes shown below. A broad range of arenes may be prepared startingfrom functionalized halo-aromatic starting materials (e.g. see below).An example synthesis of targets (I) commences with condensation ofketone E with lithiated 2-chlorothiazole to introduce the2-choro-5-thiazole moiety in 1. Similar methodologies may be employed toprepare other naphthalene targets from ketone intermediate E.

Examples 1 and 2

To a stirred solution of 2,3-dihydroxy-naphthalene (10.0 g, 0.06 mol) inDMF (100 mL) was added K₂CO₃ (45.6 g, 0.33 mol) portion wise at roomtemperature under N₂ atmosphere. The reaction mixture was then cooled to0° C. to −5° C., methyl iodide (28 g, 0.19 mol) was added drop wise overa period of 30 min at same temperature. After completion of addition,the reaction mixture was allowed to warm to room temperature and stirredfor 16 h at RT. The reaction mixture was quenched with cold water andstirred for 20 min. The precipitated solid was filtered, washed withwater (2×50 mL) and dried under vacuum to obtain D (8.0 g, 69%) as whitesolid. ¹H NMR (200 MHz, CDCl₃): δ 7.71-7.66 (m, 2H), 7.35-7.31 (m, 2H),7.12 (s, 2H), 4.0 (s, 6H). MS (ESI): m/z 189 [M⁺+1].To a mixture of D (8.5 g, 45.2 mmol) and isobutyryl chloride (6.9 g,65.5 mmol) in DCM (45 mL) was added AlCl₃ (10.1 g, 76.3 mmol)portion-wise at 0° C. to −5° C. over a period of 20 min under N₂atmosphere. After completion of addition, the reaction mixture wasallowed to warm to room temperature and stirred for 3 h. The progress ofthe reaction was monitored by TLC. The reaction mixture was quenchedwith cold water (100 mL) and 1 N HCl (50 mL) and then aqueous layer wasextracted with DCM (2×200 mL). Combined organic extracts were washedwith 1 M NaOH solution (100 mL), water (100 mL), brine (100 mL) anddried over anhydrous Na₂SO₄. After filtration and evaporation underreduced pressure, the crude material was recrystallized from ethylacetate/hexane (1:3) to afford compound-E (3.5 g, 30%) as light yellowcolored solid. ¹H NMR (200 MHz, CDCl3): δ 8.34 (s, 1H), 7.93 (d, J=10.4Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.23 (s, 1H), 7.15 (s, 1H), 4.03 (s,6H), 3.73-3.63 (m, 1H), 1.29 (d, J=7.0 Hz, 6H). MS (ESI): m/z 259[M⁺+1].

1-(2-Chloro-thiazol-5-yl)-1-(6,7-dimethoxynaphthalen-2-yl)-2-methylpropan-1-ol(1)

To a stirred solution chloro thiazole (0.18 g, 1.55 mmol) in THF (5 mL)was added n-BuLi (0.19 g, 3.1 mmol) drop wise at −70° C. under inertatmosphere. After being stirred for 1 h at −70° C., isopropyl ketone E(0.20 g, 0.77 mmol) in THF (5 mL) was added to reaction mixture at −70°C. and stirred for additional 30 min at −70° C. Allowed the reactionmixture to warm to RT and stirred for 2 h. The reaction mixture wasquenched with saturated NH₄Cl and extracted with ethyl acetate (3×50mL). The combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudematerial was purified by column chromatography eluting with 5%acetone/hexane to afford alcohol 1 (0.07 g, 0.18 mmol, 23%) as whitesolid. ¹H NMR (500 MHz, CD₃OD): δ 7.88 (s, 1H), 7.68 (d, J=8.5 Hz, 1H),7.53 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.23 (s, 1H), 7.21 (s, 1H), 3.94(s, 3H), 3.93 (s, 3H), 2.79-2.76 (m, 1H), 1.04 (d, J=6.5 Hz, 3H), 0.83(d, J=6.5 Hz, 3H). Mass: m/z: 378 [M+1].

1-(6,7-dimethoxynaphthalen-2-yl)-2-methyl-1-(thiazol-5-yl)propan-1-ol(2)

To a stirred solution of alcohol 1 (0.07 g, 0.18 mmol) in ethanol (10mL) were added sodium acetate (10 mg, 0.12 mmol) followed by addition of10% Pd/C (60 mg) at RT under inert atmosphere. The reaction mixture wasstirred at RT for 2 h under H₂ atmosphere (30 psi). Progress of reactionwas monitored by TLC. The reaction mixture was filtered through a pad ofcelite and celite bed was washed with ethanol (2×10 mL). The filtratewas concentrated under reduced pressure to afford 2 (50 mg, 0.15 mmol,78%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.75 (s, 1H), 7.88 (s,1H), 7.85 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.13(s, 1H), 7.09 (s, 1H), 3.99 (s, 6H), 2.84-2.78 (m, 1H), 1.06 (d, J=6.5Hz, 3H), 0.87 (d, J=6.5 Hz, 3H). Mass: m/z: 344 [M+1]. HPLC: 99.65%.

Example 3 Metalloenzyme Selectivity A. Inhibition of Liver CytochromeP450 Enzymes

Solutions of each test compound were separately prepared atconcentrations of 20000, 6000, 2000, 600, 200, and 60 ρM by serialdilution with DMSO:MeCN (50:50 v/v). The individual test compoundsolutions were then diluted 20-fold with DMSO:MeCN:deionized water(5:5:180 v/v/v) to concentrations of 1000, 300, 100, 30, 10, and 3 μM.Mixtures of isozyme inhibitors (sulfaphenazole, tranylcypromine, andketoconazole as specific inhibitors of isozymes 2C9, 2C19, and 3A4,respectively) were prepared containing each inhibitor at concentrationsof 6000, 2000, 600, 200, 60, 20, 6, and 2 μM by serial dilution withDMSO: ACN (50:50 v/v). The mixed inhibitor solutions were then diluted20-fold with DMSO:MeCN:deionized water (5:5:180 v/v/v) to concentrationsof 300, 100, 30, 10, 3, 1, 0.3, and 0.1 μM. The percent of organicsolvent attributable to the test compound or inhibitor mixture in thefinal reaction mixture was 2% v/v.

Pooled human liver microsome suspension (20 mg/mL) was diluted withphosphate buffer to obtain a 5 mg/mL suspension. A solution of NADPH wasprepared in phosphate buffer at a concentration of 5 mM. Separate stocksolutions of each substrate were prepared in DMSO:MeCN (50:50 v/v),mixed, and diluted in phosphate buffer to obtain a single solutioncontaining each substrate at five times its experimentally determinedK_(m) concentration. The percent of organic solvent attributable tosubstrate mixture in the final reaction mixture was 1% v/v.

Substrate solution and microsome suspension were combined in a 1:1volume ratio, mixed, and distributed to reaction wells of a PCR plate.Individual test compound or combined inhibitor solutions at eachconcentration were added to the wells and mixed by repetitiveaspirate-dispense cycles. For active controls, blank phosphate buffersolution was added in place of test compound solution. Reaction mixtureswere allowed to equilibrate at 37° C. for approximately two minutesbefore adding NADPH solution to initiate reaction, followed by pipettemixing of reaction mixture. Ten minutes after addition of NADPH, thereaction mixtures were quenched with cold acetonitrile. The samples weremixed by orbital shaking for approximately one minute and centrifuged at2900 RCF for ten minutes. A portion of the supernatant was analyzed bygradient reverse-phase HPLC with detection by electrospray ionizationtriple quadrupole mass spectrometry in the positive ion mode. Data wasfitted to sigmoid dose-response curves and the inhibitory potency ofeach test compound was determined as its IC₅₀ value.

Example 4 CYP17 Metalloenzyme Activity

CYP17 activity was assayed according to the following procedure.Solutions of each test compound and isozyme inhibitor (ketoconazole)were separately prepared at concentrations of 2700, 540, 90, 18, 3, 0.6and 0.1 μM by serial dilution with DMSO:ACN (50:50 v/v). The individualtest compound and isozyme inhibitor solutions were then diluted 20-foldwith deionized water (50:950 v/v) to concentrations of 135, 27, 4.5,0.9, 0.15, 0.03 and 0.005 μM. The percent of organic solventattributable to the test compound or inhibitor mixture in the finalreaction mixture is 1%. Pooled rat testicular microsome suspension (20mg/mL) was diluted with phosphate buffer to obtain a 1.25 mg/mLsuspension. A solution of NADPH was prepared in phosphate buffer at aconcentration of 2.5×. A stock solution of the substrate was prepared inDMSO:MeCN (50:50 v/v), mixed, and diluted in phosphate buffer to obtaina single solution containing the substrate at 5 μM. The percent oforganic solvent attributable to substrate mixture in the final reactionmixture is 1%. Substrate solution and microsome suspension were combinedin a 1:1 volume ratio, mixed, and distributed to reaction wells of a PCRplate. Individual test compound or the inhibitor solution at eachconcentration was added to the wells and mixed by repetitiveaspirate/dispense cycles. For active controls, blank test compounddiluent was added in place of test compound solution. Reaction mixtureswere allowed to equilibrate at 37° C. for approximately two minutesbefore adding NADPH solution to initiate reaction, followed by pipettemixing of reaction mixture. Compounds of the presently disclosed subjectmatter exhibit IC50s in the range shown in Table 1.

TABLE 1 CYP17 results Example CYP17 IC50* CYP2C9* CYP2C19* CYP3A4* 20.29 33 3.0 0.77 Ketoconazole 0.40 40 19 0.15 *CYP IC50 values areexpressed in uM.

INCORPORATION BY REFERENCE

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. Such equivalents areintended with be encompassed by the following claims.

What is claimed is:
 1. A compound of formula (II):

wherein R₂ is optionally substituted aryl, optionally substitutednaphthyl, optionally substituted heteroaryl, optionally substitutedalkyl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, or optionallysubstituted heteroaryl-alkyl; R₃ is H, OH, alkoxy, amino, alkylamino, ordialkylamino; R₄ is chloro; R₅ is halogen, alkoxy, fluoroalkoxycontaining 1-5 fluorines, cyano, carboxamido, optionally substitutedaryl, or optionally substituted heteroaryl; and R₆ is H, halogen,alkoxy, fluoroalkoxy containing 1-5 fluorines, cyano, carboxamido,optionally substituted aryl, or optionally substituted heteroaryl.
 2. Acompound that is:1-(2-Chloro-thiazol-5-yl)-1-(6,7-dimethoxynaphthalen-2-yl)-2-methylpropan-1-ol  (1);or1-(6,7-dimethoxynaphthalen-2-yl)-2-methyl-1-(thiazol-5-yl)propan-1-ol  (2).3. A method of treating a subject suffering from a metalloenzyme-relateddisorder or disease, wherein the subject has been identified as in needof treatment for a metalloenzyme-related disorder or disease, comprisingadministering to said subject in need thereof, an effective amount of acompound of claim 1, such that said subject is treated for saiddisorder; wherein the disease or disorder is prostate cancer, breastcancer, testicular cancer, uterine cancer, or ovarian cancer.
 4. Themethod of claim 3, wherein the disease or disorder is prostate cancer.5. A composition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 6. The composition of claim 5 further comprising anadditional therapeutic agent.
 7. The composition of claim 6 furthercomprising an additional therapeutic agent that is an anti-cancer agent,antifungal agent, cardiovascular agent, antiinflammatory agent,chemotherapeutic agent, an anti-angiogenesis agent, cytotoxic agent, ananti-proliferation agent, metabolic disease agent, opthalmologic diseaseagent, central nervous system (CNS) disease agent, urologic diseaseagent, or gastrointestinal disease agent.
 8. The compound of claim 1,wherein R₃ is OH.
 9. The compound of claim 1, wherein R₂ is optionallysubstituted alkyl and R₃ is OH.
 10. The compound of claim 1, wherein R₂is alkyl and R₃ is OH.